The molecular pathways involved in proliferative disorders and oncogenesis often represent aberrations of processes that normally occur during embryogenesis. One such pathway implicated in proliferative disorders such as cancer is the evolutionally conserved gene network termed the retinal determination gene network, or “RDGN.”
The Six and Eya families of genes are frequently found upregulated in cancers. However, the molecular mechanisms by which the protein products of these genes might effect cancer development or progression has not been sufficiently described to allow the identification of novel therapeutics that can be used to treat proliferative disorders such as cancer. As such, current methods of measuring Eya activity and the effect of this protein on cell proliferation, migration and growth have not been successfully used to identify novel molecules for treatment of proliferative disorders.
The Eya protein, a member of the RDGN, has been shown to be a protein tyrosine phosphatase (PTP). While PTPs in general are emerging as important new targets for cancer therapy (reviewed in 15), PTPs as a target have limitations that confound the practical utility of this approach. Because PTPs share a common, thiol-based mechanism, the design of PTP inhibitors has been hampered by the inability to achieve specificity among the large family of mammalian PTPs. Due to the conserved regions of the active site among PTPs, particularly the conserved catalytic cysteine residue, targeting specific PTPs has proved difficult. Furthermore, most potent PTP inhibitors identified to date tend to be phospho-tyrosine mimics that have poor cell-permeability and other pharmaceutical properties, thus making them unsuitable for effective therapeutic use in treating proliferative disorders.
Anti-vascular therapy has emerged as an extremely promising option for the treatment of several major diseases including solid tumors and the vision-compromising ailments diabetic retinopathy, age-related macular degeneration (AMD) and retinopathy of prematurity. The protein tyrosine phosphatases (PTPs) of the Eyes Absent family are highly likely to be useful drug targets in anti-vascular therapy. Eyes Absent phosphatases are expressed in vascular endothelial cells (VECs) and the phosphatase activity enhances cell migration and the formation of vessel-like structures in culture.
Agents that specifically target PTPs have enormous potential in the treatment of proliferative, invasive and/or metastatic, angiogenic and/or vascular disorders such as cancer, given the significant increase in PTP activity in many disease states. Though approximately 30% of cellular proteins are phospho-proteins, tyrosine phosphorylation accounts for only about 0.01% to about 0.05% of all phospho-proteins. In disease states such as oncogenic transformation, however, tyrosine phosphorylation is increased up to one to two hundred-fold to 1 to 2% of the total phospho-protein population. While protein tyrosine phosphatases have been extensively linked with disease states including proliferative diseases such as cancer, the design of tyrosine phosphatase inhibitors, as discussed above, has traditionally been confounded by a lack of specificity, and there remains a significant need in identifying PTP specific inhibitors for the treatment of disorders involving PTP dysregulation.
Thus, there exists a need in the art for inhibitors with no inhibitory activity toward the large family of classical PTPs. The methods of the instant invention seek to address this limitation in the art.